There are still few reliable and simple methods of vaccination in which the resulting immunity is operationally programmable, restricted to possibly one cell type functioning as antigen producing and antigen presenting cell, and endowed with self-amplifying/self-renewing capacity. This type of vaccine could be of extreme value against cancer.For the past years this laboratory has worked towards developing such a new approach. We established that an adult immunocompetent animal can readily be immunized with a single injection of syngeneic lymphocytes made transgenic in vitro for immunoglobulin (Ig) genes controlled by a B cell specific promoter for targeted expression in B lymphocytes. The Ig genes are themselves engineered to code for heterologous epitopes to confer antigen specificity. Since B lymphocytes are excellent Ig producers and present Ig peptides to CD4 and CD8 T cells very efficiently, transgenic lymphocytes are a novel form of cell vaccine in which endogenous synthesis of antigen and antigen presenting cell (APC) function are ideally combined. We term this process Transgenic Lymphocyte Immunization (TLI). Our preliminary data indicate that these events occur with high fidelity and at high immunological efficiency. TLI lends itself to a robust antigen-specific CD4 and CTL responses with a single injection of as few as 70 transgenic cells. New data provided in the revised application also demonstrate that TLI generates T cell immunity against sub-immungenic epitopes and that the ensuing immunity is highly effective (>85 percent) in tumor protection. The work proposed is built on the hypothesis that B lymphocytes are key to TLI. It is our goal to: (1) elucidate the basic mechanisms of TLI for the induction of antigen-specific CD4 and CD8 responses; (2) compare TLI to vaccination with dendritic cells (DC); and (3) test TLI ability to protect in animal models of tumor. Current vaccines need to be improved with respect to their ability to generate the type of immunity needed to (a) enhance natural defenses or train the immune system to develop new ones, and (b) keep the balance between the tumor growth kinetics and the host immune response in favor of the immune response. We believe that TLI is a simple and effective form of APC vaccine that can meet this need and objectives.